J. W. C. Crawford (1967), J. Chem. Soc. (C) 2332–2333, described a method for producing (S)-1,1,1-trifluoro-2-propanol, where (±)-1-(trifluoromethylethoxy) propionic acid (the adduct of the alcohol and acrylic acid) was separated into its optical isomers through its quinine salt, and pure (S)-1,1,1-trifluoro-2-propanol was obtained from the enantiomeric pure alkoxy-acid by alkaline hydrolysis and distillation. Although this method affords (S)-1,1,1-trifluoro-2-propanol of high enantiomeric purity (optical rotation: −5.65°), the method is not suitable for large scale production.
T. C. Rosen et al. (2004), Chimica Oggi Suppl., 43–45 , prepare both (R)- and (S)-1,1,1-trifluoro-2-propanol by asymmetric reduction of 1,1,1-trifluoroacetone using alcohol dehydrogenases (ADHs) either in their natural hosts or as recombinant enzymes expressed in E. coli. Resting whole cells or crude cell free extracts may be used and in the latter case addition of a cofactor regenerating system is necessary. The resulting (S)-1,1,1-trifluoro-2-propanol is available for purchase at Jülich Fine Chemicals, but the material offered is of insufficient enantiomeric purity (>92.5% ee) for our needs.
M. Buccierelli et al. (1983), Synthesis 11, 897–899, describe the preparation of (S)-1,1,1-trifluoro-2-propanol by reduction of 1,1,1-trifluoroacetone using (resting) Baker's yeast on lab scale. Although the reaction proceeds fast (4 hours), a 300 times excess of yeast with respect to substrate is required, the substrate concentration is only 2.5 g/kg yeast suspension, and (S)-1,1,1-trifluoro-2-propanol is obtained only with approx. 80% ee (as calculated from the optical rotation of −4.5° for the isolated alcohol, compared with −5.6° for the pure alcohol), a value which is far too low for our needs. In addition, the isolation protocol, based on repeated solvent extraction in combination with distillation, is not applicable economically on large scale.
There are several methods used in literature to optimize the stereoselectivity of microbial reductions, e.g. acetone treatment of the microbial cells or performing the biotransformation in organic solvents. Both methods have the disadvantages that using solvents makes a process more costly and, more important, the solvent used further complicates the already demanding procedure for the isolation of (S)-1,1,1-trifluoro-2-propanol, which possesses a boiling point of 76–77 ° C.
Another method to increase the stereoselectivity is using inhibitors to block the enzyme(s) affording the unwanted isomer. A. C. Dahl et al. (1999), Tetrahedron: Asymmetry 10, 551–559, reported the reduction of ethyl-3-oxopentanoate with non heat-treated Baker's yeast and allyl alcohol to ethyl-3(R)-hydroxy-pentanoate (100% yield and 92–93 % ee). When heat-treated Baker's yeast (48° C. for 60 min) was used in combination with allyl alcohol the product was obtained in 80–95% yield and the ee was increased to 98%. However, for the successful reaction a substrate concentration of approximately 1 g/L was used and 250 times yeast relative to substrate, respectively 4 times inhibitor relative to substrate were required.
Another method to influence the stereoselectivity of a microbial reduction is to perform a heat treatment of the microbial cells, to inactivate the enzymes affording the non-wanted stereoisomer. Y. Yasohara et al. (1999), Appl. Microbiol. Biotechnol. 51, 847–851 , investigated the reduction of ethyl 4-chloro-3-oxobutyrate (COBE) to 4-chloro-(S)-3-hydroxybutyrate (CHBE) with various yeasts. Acetone treated cells of Candida magnolia converted COBE in 75% molar yield to (S)—CHBE with 91.0% ee. When the cells of C. magnolia were heat treated (60° C.), (S)—CHBE was obtained in 75% yield with >98% ee. On the other side, when acetone treated cells of Saccharomyces cerevisiae were used (non-heat treated), (S)—CHBE was obtained in 53% molar yield and only with 14.8% ee. After heat treatment cells of S. cerevisiae at 50° C., (S)—CHBE was obtained in only 10% yield with 53.8% ee. (S)—CHBE was obtained with >98% ee after heat treatment at 60° C. (8% yield). On a preparative scale, using C. magnoliae, 90 g/L COBE was converted quantitatively to (S)—CHBE with 96.6% ee within 60 hours, respectively in 97% yield and with >99% ee, using heat treated cells. The reaction was performed in a two phase system with n-butyl acetate and required a coenzyme-regenerating system (glucose, NAD(P) and glucose dehydrogenase). The requirement for a cofactor regenerating system based on glucose dehydrogenase is due to inactivation of endogenous enzymes by acetone treatment.
Z. H. Yang et al (2004), Ind. Eng. Chem. Res. 43, 4871–4875, described also the asymmetric reduction of COBE to (S)—CHBE catalyzed by yeast. By heat treatment of the yeast (50° C.) the ee of (S)—CHBE increased from 84% to 97%, with an increase in the pretreatment time from 30 to 120 min. On the other hand the conversion of COBE decreased from 96% to 82%. Glucose was used to regenerate NAD(P) to NAD(P)H. The reaction was performed with yeast from dried baker's yeast. The described procedure is not useful and economic for using on large scale.
K. Nakamura et al. (1996), Tetrahedron: Asymmetry 7, 409–412 , described the yeast reduction of α-diketones to the corresponding hydroxyketo compounds, where the heat treatment influenced the regioselectivity of the reaction. Although, for example, the reduction of 1-phenyl-1,2-propanedione with heat treated yeast afforded 1-phenyl-2-hydroxy-1-propanone in 80% yield and >98% ee, the reaction required a relatively large amount of yeast (30 times relative to the substrate).